The goal of this application is to support my professional development as a clinical investigator and a mentor to junior faculty and fellows interested in patient-oriented research. My research has focused on the in depth investigation of various disease states and medications and their effects on bone mass, bone remodeling and mineral metabolism. This proposal stems from preliminary work that has begun to elucidate the pathogenesis of idiopathic osteoporosis (IOP) in pre-menopausal women. Transiliac crest bone biopsies from a small number of such women have revealed uncoupled remodeling, with increased bone resumption and markedly decreased formation. The hypothesis of this proposal is that IOP in premenopausal women is a disorder characterized by abnormal skeletal micro architecture and remodeling, in which there is uncoupling of formation from resumption, the imbalance favoring resumption. I will test this hypothesis in a cross-sectional study in which premenopausal women with IOP will be compared to normal women. Other goals are to investigate the etiology and pathogenesis and to assess various measures of bone quality in women with IOP. The five specific aims are to: 1. Describe the clinical phenotype. 2: Define the relationship between central and peripheral volumetric measurements of bone mineral density and fracture prevalence. 3: Define pathogenesis abnormalities in bone utilizing quantitative histomorphometry, micro-CT, micro-FE and FTIRI. 4: Characterize estrogen status, and 5: Elucidate biochemical characteristics that may contribute to the pathogenesis. The results should have important therapeutic implications for the diagnosis and management of IOP in premenopausal women. Importantly, the proposal will provide many opportunities to mentor beginning junior investigators. I have had excellent success as a mentor, with two recent K-23 awardees and 16 former or current trainees. There has been significant interest in my research from Endocrine Fellows and from Fellows and junior faculty in other disciplines. The Department of Medicine and the GCRC have made substantial commitments toward my development as a clinical investigator. However, it is clearly necessary for me to reduce my clinical, administrative and teaching loads in order to devote sufficient time to clinical research and to training and mentoring junior faculty and fellows. The K24 award is the ideal mechanism to ensure the support essential for my continued success as a mentor and patient-oriented investigator.